Method of inhibiting gastro-intestinal irritation



United States Patent Ofiice 3,129,137 Patented Apr. 14, 1964 3,129,137 METHOD OF INHIBITING GASTRO-IN'IESTINAL IRRITATION Karl H. Beyer, Gwynedd Valley, Pa, assignor to Merck dz End, Rahway, NJ, a corperation of New Jersey No Drawing. Filed Mar. 30, 1961, Ser. No. 99,370 9 Claims. ((31. 167-55) This invention relates to pharmaceutical formulations. In particular, it is concerned with formulations containing certain lower alkyl substituted tertiary pentanol carbamate compounds having muscle relaxing and tranquil- 1z1ng properties.

These carbamate compounds can be identified as lower alkyl substituted tertiary pentanol carbamates of the formu a wherein R and R are alkyl substituents having a combined total of 4 carbon atoms and R is an alkyl group containing no more than 2 carbon atoms. Illustrative of these compounds, there may be mentioned 3-methyl-3- pentanol carbamate, 3-ethyl-3-pentanol carbamate and 2- methyl-Z-pentanol carbamate. These compounds may be prepared in the manner described in U.S. Patent No. 2,972,564.

The active muscle relaxing and tranquilizing compounds described above have heretofore been found effective when administered orally, parenterally or rectally. However, because of the limited solubility of these compounds in water, parenteral administration is not particularly desirable. On the other hand, rectal administration is not always desirable for obvious reasons. Consequently, the preferred mode of administration is via the oral route. Unfortunately, however, it has been found that these compounds cause a significant amount of gastro-intestinal irritation, as evidenced by frequent eructation, when administered orally at the recommended dosage levels. This, of course, is both annoying and discomforting to one taking such medication. Obviously, then, oral preparations containing these compounds which are free from this undesirable side effect Without sacrificing any therapeutic effect would be most welcomed by the medical profession.

According to the present invention, it has been found that the gastro-intestinal irritation and resulting eructation associated with the oral administration of the above-mentioned compounds can be virtually eliminated without sacrificing therapeutic benefit by the concurrent oral administration with the active ingredient of from about 0.5 to about 2.5 mg. of glycine per mg. of active ingredient. Preferably, however, the amount of glycine employed is of the order of from about 1.0 to about 1.5 mg. per mg. of active ingredient.

In clinical use, the recommended dosage of the active ingredient is 50 to 800 mg, preferably 100 to 400 mg. of active ingredient 2 to 4 times per day. Accordingly, for convenience of administration, and for assurance that the aforementioned ratio and dosage requirements are met in routing therapy, the active ingredient and glycine are provided in a unitary form for administration, preferably intermixed as a single composition, and preferably, also, either in dosage unit form, such as tablets, capsules, elixirs, suspensions and the like or in a form readily subdivided into unit doses. However, it is to be understood that the glycine and carbamate compound may, if desired, be administered separately. In such instances either com ponent may be admininstered first, followed shortly thereafter by the administration of the other.

In the preparation of solid orally administrable compositions contemplated by the present invention, the active ingredient and glycine are intimately admixed and the resulting mixture either dry filled into capsules or with the aid of suitable excipients such as binders, lubricants, disintegrating agents, fillers and the like, compressed into suitable tablets, pills, pellets, using conventional formulating techniques. Similarly, various orally administrable liquid formulations can be readily prepared with the aid of suitable dispersing agents, suspending agents, emulsifying agents and the like.

The following examples show the preparation of typical orally administrable formulations of the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1.Tablets Example Z.Capsules A mixture-is prepared containing 400 g. of 3-methyl- 3-pentanol carbamate and 500 g. of glycine. This mixture is then filled, 450 mg. per capsule, into standard gelatin capsules. The resulting capsules contain per dosage unit 200 mg. of the carbamate and 250 mg. of glycine.

Example 3.Elixirs An elixir is prepared containing per liter:

3-methyl-3-pentanol carbamate g- 40.0 Glycine g 50.0 Ethyl alcohol ml 175.0 Glycerin ml 500.0 Methyl parabens g 1.0 Propyl parabens g 0.5 Saccharin sodium ..g 2.0 Sodium citrate g 2.0 Sorbitol (70% solution) ml 275.0

Distilled water, q.s.

The carbamate, methyl parabens and propyl parabens are dissolved in the alcohol and the glycerin and sorbitol are added. The glycine, saccharin and citrate are dissolved in a small amount of water. The aqueous solution is then added to the alcohol solution and the balance of the water is added to bring the volume to 1 liter. After mixing and filtering an elixir is obtained containing 40 mg. of the carbamate and 50 mg. of glycine per ml. A unit dose of 5 m1. (1 teaspoon) thus contains 200 mg. of carbamate and 250 mg. of glycine.

In the foregoing examples it will be understood that other carbamates such as 3-ethyl-3-pentanol carbamate or Z-methyl-Z-pentanol carbamate can be substituted for the 3-methyl-3-pentanol carbamate as the active component, and that the amount of active component can be suitably varied within the range of 50-800 mg., and preferably to 400 mg. per dosage unit.

Various changes and modifications of the invention can be made, and to the extent that such variations incorporate the spirit of the instant invention, they are intended to be included within the scope of the appended claims.

wherein R and R are alkyls having a combined total of 4 carbon atoms and R is an alkyl containing no more than 2 carbon atoms, said glycine being present in said composition in an amount of from about 0.5 mg. to about 2.5 mg. per mg. of carbamate.

2. A therapeutic composition comprising glycine and a carbamate of the formula wherein R and R are alkyls having a combined total of 4 carbon atoms and R is an alkyl containing no more than 2 carbon atoms, said glycine being present in said composition in an amount of from about 1.0 mg. to about 1.5 mg. per mg. of carbamate.

3. The composition of claim 2, wherein the carbamate is 3-methyl-3-pentanol carbamate.

4. The composition defined by claim 1, wherein the glycine and carbamate are incorporated in an orally administrable pharmaceutical carrier.

5. The composition defined by claim 4, wherein the carrier is an orally administrable solid pharmaceutical carrier.

6. The composition defined by claim 4, wherein the carrier is an orally administrable liquid pharmaceutical carrier.

7. A method of inhibiting gastro-intestinal irritation and resulting eructation associated with the oral administration of a carbamate of the formula O Elk-NH;

wherein R and R are alkyls having a combined total of 4 carbon atoms and R is an alkyl containing no more than 2 carbon atoms, which comprises orally administering said carbamate and in addition thereto from about 0.5 to about 2.5 mg. of glycine per mg. of carbamate.

8. A method of inhibiting gastro-intestinal irritation and resulting eructation associated with the oral administration of a carbamate of the formula o pawn,

wherein R and R are alkyls having a combined total of 4 carbon atoms and R is an alkyl containing no more than 2 carbon atoms, which comprises orally administering said carbamate and in addition thereto glycine in an amount sufiicient to inhibit said gastro-intestinal irritation and eructation.

9. A method of inhibiting gastro-intestinal irritation and resulting eructation associated with the oral administration of a carbamate of the formula 2 0 (If-NH:

wherein R and R are alkyls having a combined total of 4 carbon atoms and R is an alkyl containing no more than 2 carbon atoms, which comprises orally administering said carbamate and in addition thereto glycine in an amount of at least 0.5 mg. per mg. of said carbamate.

References Cited in the file of this patent UNITED STATES PATENTS 2,283,817 Martin May 19, 1942 2,376,795 Martin et a1. May 22, 1945 2,429,596 Abramson Oct. 28, 1947 2,972,564 Melander Feb. 21, 1961 FOREIGN PATENTS 564,154 Great Britain Sept. 14, 1944 OTHER REFERENCES Melander: J. of Med. and Pharm. Chem., vol. 1, No. 5, pp. 443-457, 1959.

Williams: Detoxication Mechanisms, Wiley, 1959, pp. 161-163, p. 7, p. 350.

Dispensatory of U.S., 25th ed., part. 1, 1955, pp. 62-63. 

1. A THERAPEUTIC COMPOSITION COMPRISING GLYCINE AND A CARBAMATE OF THE FORMULA R1-C(-R2)(-R3)-OOC-NH2 WHEREIN R1 AND R2 ARE ALKYLS HAVING A COMBINED TOTAL OF 4 CARBON ATOMS AND R3 IS AN ALKYL CONTAINING NO MORE THAN 2 CARBON ATOMS, SAID GLYCINE BEING PRESENT IN SAID COMPOSITION IN AN AMOUNT OF FROM ABOUT 0.5 MG. TO ABOUT 2.5 MG. PER MG. OF CARBAMATE. 